Baseline characteristics including blood and urine metal levels in the Trial to Assess Chelation Therapy 2 (TACT2).

BACKGROUND: The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. METHODS: TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2's participants. RESULTS: At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. CONCLUSIONS: TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185.

Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.

INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

Association between chiropractic spinal manipulation and gabapentin prescription in adults with radicular low back pain: retrospective cohort study using US data.

OBJECTIVES: Radicular low back pain (rLBP) is often treated off-label with gabapentin or by chiropractors using chiropractic spinal manipulative therapy (CSMT). To date, no studies have examined the association between these interventions. We hypothesised that adults under 50 years of age receiving CSMT for newly diagnosed rLBP would have reduced odds of receiving a gabapentin prescription over 1 year-follow-up. DESIGN: Retrospective cohort study. SETTING: US network including linked medical records, medical claims and pharmacy claims of >122 million patients attending large healthcare organisations (TriNetX), queried 15 June 2023, yielding data from 2017 to 2023. PARTICIPANTS: Adults aged 18-49 were included at their first occurrence of rLBP diagnosis. Exclusions were severe pathology, other spinal conditions, on-label gabapentin indications and gabapentin contraindications. Propensity score matching controlled for variables associated with gabapentin use and receipt of prescription medication over the preceding year. INTERVENTIONS: Patients were divided into CSMT or usual medical care cohorts based on the care received on the index date of rLBP diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: OR for gabapentin prescription. RESULTS: After propensity matching, there were 1635 patients per cohort (mean age 36.3±8.6 years, 60% women). Gabapentin prescription over 1-year follow-up was significantly lower in the CSMT cohort compared with the usual medical care cohort, with an OR (95% CI) of 0.53 (0.40 to 0.71; p<0.0001). Sensitivity analyses revealed early divergence in cumulative incidence of prescription; and no significant between-cohort difference in a negative control outcome (gastrointestinal medication) suggesting adequate control for pharmacological care preference. CONCLUSIONS: Our findings suggest that US adults receiving CSMT for newly diagnosed rLBP have significantly reduced odds of receiving a gabapentin prescription over 1-year follow-up compared with those receiving usual medical care. Results may not be generalisable and should be replicated in other healthcare settings and corroborated by a prospective study to reduce confounding.

Antagonistic circuits mediating infanticide and maternal care in female mice.

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state1,2. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring3,4. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits5,6, we use the medial preoptic area (MPOA), a key site for maternal behaviours7-11, as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTprESR1) are necessary, sufficient and naturally activated during infanticide in female mice. MPOAESR1 and BNSTprESR1 neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOAESR1 and BNSTprESR1 cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young.

Transcriptomic Profiling and Pathway Analysis of Mesenchymal Stem Cells Following Low Dose-Rate Radiation Exposure.

Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1-2 Gy, 0.66 cGy/h, 60Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation.

Positive psychological well-being: A novel concept for improving symptoms, quality of life, and health behaviors in irritable bowel syndrome.

BACKGROUND: Though a growing body of research suggests that greater positive psychological well-being in irritable bowel syndrome (IBS) may be protective, existing brain-gut behavior therapies primarily target negative psychological factors. Little is known about how positive psychological factors in IBS relate to IBS symptoms, health-related quality of life (HRQoL), or adherence to key health behaviors, such as physical activity and diet modification. Accordingly, per the ORBIT model of behavioral treatment development for chronic diseases, we explored potential connections between psychological constructs and IBS symptoms, health behavior engagement (physical activity and dietary modification), and HRQoL in a qualitative study to inform the development of a novel brain-gut behavior therapy. METHODS: Participants with IBS completed self-report assessments and semi-structured phone interviews about relationships between positive and negative psychological constructs, IBS symptoms, health behavior engagement, and HRQoL. KEY RESULTS: Participants (n = 23; 57% female) ranged in age from 25 to 79 (mean age = 54). IBS subtypes were similarly represented (IBS-diarrhea [n = 8], IBS-constipation [n = 7], and IBS-mixed [n = 8]). Participants described opposing relationships between positive and negative psychological constructs, IBS symptoms, health behavior engagement, and HRQoL, respectively, such that experiencing positive constructs largely mitigated IBS symptoms, boosted health behavior participation, and improved HRQoL, and negative constructs exacerbated symptoms, reduced health behavior participation, and worsened HRQoL. CONCLUSIONS AND INFERENCES: Participants with IBS linked greater positive psychological well-being to moderated IBS symptoms and better HRQoL and health behavior participation. An intervention to cultivate greater well-being may be a novel way to mitigate IBS symptoms, boost health behavior participation, and improve HRQoL in IBS.

Positive psychological well-being and clinical characteristics in IBS: A systematic review.

OBJECTIVE: Psychological factors (e.g., depression, anxiety) are known to contribute to the development and maintenance of irritable bowel syndrome (IBS). Less is known, however, about the role of positive psychological well-being (PPWB) in IBS. Accordingly, we completed a systematic review of the literature examining relationships between PPWB and clinical characteristics in IBS. METHOD: A systematic review using search terms related to PPWB and IBS from inception through July 28, 2022, was completed. Quality was assessed with the NIH Quality Assessment Tool. A narrative synthesis of findings, rather than meta-analysis, was completed due to study heterogeneity. RESULTS: 22 articles with a total of 4285 participants with IBS met inclusion criteria. Individuals with IBS had lower levels of PPWB (e.g., resilience, positive affect, self-efficacy, emotion regulation) compared to healthy populations, which in turn was associated with reduced physical and mental health and health-related quality of life (HRQoL). Limited exploration of potential biological mechanisms underlying these relationships has been described. CONCLUSIONS: PPWB is diminished in individuals with IBS compared to other populations, and greater PPWB is linked to superior physical, psychological, and HRQoL outcomes. Interventions to increase PPWB may have the potential to improve IBS-related outcomes. REGISTRATION: Prospective Register of Systematic Reviews CRD42022304767.

Association between chiropractic spinal manipulation and lumbar discectomy in adults with lumbar disc herniation and radiculopathy: retrospective cohort study using United States' data.

OBJECTIVES: Chiropractic spinal manipulative therapy (CSMT) and lumbar discectomy are both used for lumbar disc herniation (LDH) and lumbosacral radiculopathy (LSR); however, limited research has examined the relationship between these therapies. We hypothesised that adults receiving CSMT for newly diagnosed LDH or LSR would have reduced odds of lumbar discectomy over 1-year and 2-year follow-up compared with those receiving other care. DESIGN: Retrospective cohort study. SETTING: 101 million patient US health records network (TriNetX), queried on 24 October 2022, yielding data from 2012 query. PARTICIPANTS: Adults age 18-49 with newly diagnosed LDH/LSR (first date of diagnosis) were included. Exclusions were prior lumbar surgery, absolute indications for surgery, trauma, spondylolisthesis and scoliosis. Propensity score matching controlled for variables associated with the likelihood of discectomy (eg, demographics, medications). INTERVENTIONS: Patients were divided into cohorts according to receipt of CSMT. PRIMARY AND SECONDARY OUTCOME MEASURES: ORs for lumbar discectomy; calculated by dividing odds in the CSMT cohort by odds in the cohort receiving other care. RESULTS: After matching, there were 5785 patients per cohort (mean age 36.9±8.2). The ORs (95% CI) for discectomy were significantly reduced in the CSMT cohort compared with the cohort receiving other care over 1-year (0.69 (0.52 to 0.90), p=0.006) and 2-year follow-up (0.77 (0.60 to 0.99), p=0.040). E-value sensitivity analysis estimated the strength in terms of risk ratio an unmeasured confounding variable would need to account for study results, yielding point estimates for each follow-up (1 year: 2.26; 2 years: 1.92), which no variables in the literature reached. CONCLUSIONS: Our findings suggest receiving CSMT compared with other care for newly diagnosed LDH/LSR is associated with significantly reduced odds of discectomy over 2-year follow-up. Given socioeconomic variables were unavailable and an observational design precludes inferring causality, the efficacy of CSMT for LDH/LSR should be examined via randomised controlled trial to eliminate residual confounding.

Case report: Rapid onset, ischemic-type gastritis after initiating oral iron supplementation.

Oral iron supplements are commonly administered to patients with chronic iron deficiency anemia. This approach is generally well-tolerated, causing only mild adverse effects. Rarely, oral iron supplementation can cause more severe symptoms, one of the most concerning being acute gastritis. This predominantly affects elderly patients and is extremely uncommon in young, otherwise healthy people. Here, we report the case of a 43-year-old woman who presented with upper gastrointestinal (GI) symptoms and iron deficiency anemia and was started on oral iron supplementation following the resolution of her acute symptoms. She soon re-presented with a severe, Helicobacter pylori-negative gastritis with iron deposition on histology. These new onset symptoms resolved rapidly with cessation of iron supplements, consistent with iron pill gastritis. In addition to the limited body of literature describing iron pill gastritis, this case serves as a reminder that any patient receiving oral iron supplementation is at a potential risk for gastritis, particularly in the setting of an ongoing GI pathology. Hence, it is important to provide continued follow-up for patients receiving iron supplementation regardless of age or comorbidity, particularly in the weeks following the start of the treatment.

Biliary Polycyclic Aromatic Hydrocarbon Metabolite Equivalents Measured in Fish and Subtidal Invertebrates Following the Refugio Beach Oil Spill.

Monterey formation crude oil spilled from an onshore pipeline and entered the surf zone near Refugio State Beach, Santa Barbara County, CA, USA on 19 May 2015. Exposure to nearshore fish was evaluated by measuring biliary polycyclic aromatic hydrocarbon (PAH) metabolite concentrations in surfperch (Embiotocidae), collected near the release point, at a lesser oiled area, Gaviota State Beach, and near the Coal Oil Point oil seep, Campus Point, at both four days and approximately one year after the oil spill. Three to four weeks after the spill, fish, invertebrates, and kelp were collected near the same three sites for PAH analysis of edible tissues to support the fishery closure assessment. Additionally, thirteen days after the spill, vegetation, and invertebrate tissue samples from the seafloor near Refugio State Beach were analyzed for PAHs. In surfperch bile, mean naphthalene, phenanthrene and benzo(a)pyrene metabolite equivalents were significantly higher at Refugio State Beach, compared to Gaviota State Beach or Campus Point in 2015. One year later, there was no significant difference between the three sites. Spatial and depth zone patterns of PAH tissue concentrations from composited invertebrate, vegetation and fish showed highest concentrations were measured in invertebrates collected near Refugio State Beach. Overall, results show elevated PAH levels in nearshore organisms and provide a useful reference for potential PAH exposures in fish and subtidal invertebrates following a large nearshore oil spill.

Guideline-concordant utilization of magnetic resonance imaging in adults receiving chiropractic manipulative therapy vs other care for radicular low back pain: a retrospective cohort study.

BACKGROUND: Lumbar magnetic resonance imaging (LMRI) is often performed early in the course of care, which can be discordant with guidelines for non-serious low back pain. Our primary hypothesis was that adults receiving chiropractic spinal manipulative therapy (CSMT) for incident radicular low back pain (rLBP) would have reduced odds of early LMRI over 6-weeks' follow-up compared to those receiving other care (a range of medical care, excluding CSMT). As a secondary hypothesis, CSMT recipients were also expected to have reduced odds of LMRI over 6-months' and 1-years' follow-up. METHODS: A national 84-million-patient health records database including large academic healthcare organizations (TriNetX) was queried for adults age 20-70 with rLBP newly-diagnosed between January 31, 2012 and January 31, 2022. Receipt or non-receipt of CSMT determined cohort allocation. Patients with prior lumbar imaging and serious pathology within 90 days of diagnosis were excluded. Propensity score matching controlled for variables associated with LMRI utilization (e.g., demographics). Odds ratios (ORs) of LMRI over 6-weeks', 6-months', and 1-years' follow-up after rLBP diagnosis were calculated. RESULTS: After matching, there were 12,353 patients per cohort (mean age 50 years, 56% female), with a small but statistically significant reduction in odds of early LMRI in the CSMT compared to other care cohort over 6-weeks' follow-up (9%, 10%, OR [95% CI] 0.88 [0.81-0.96] P = 0.0046). There was a small but statistically significant increase in odds of LMRI among patients in the CSMT relative to the other care cohort over 6-months' (12%, 11%, OR [95% CI] 1.10 [1.02-1.19], P < 0.0174) and 1-years' follow-up (14%, 12%, OR [95% CI] 1.21 [1.13-1.31], P < 0.0001). CONCLUSIONS: These results suggest that patients receiving CSMT for newly-diagnosed rLBP are less likely to receive early LMRI than patients receiving other care. However, CSMT recipients have a small increase in odds of LMRI over the long-term. Both cohorts in this study had a relatively low rate of early LMRI, possibly because the data were derived from academic healthcare organizations. The relationship of these findings to other patient care outcomes and cost should be explored in a future randomized controlled trial. REGISTRATION: Open Science Framework ( https://osf.io/t9myp ).

The trial to assess chelation therapy 2 (TACT2): Rationale and design.

BACKGROUND: Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design. METHODS: TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are followed for 2.5 to 5 years. The primary endpoint is time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial has >;85% power to detect a 30% relative reduction in the primary endpoint. TACT2 also includes a Trace Metals and Biorepository Core Lab, to test whether benefits of treatment, if present, are due to chelation of lead and cadmium from patients. Design features of TACT2 were chosen to replicate selected features of the first TACT, which demonstrated a significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. RESULTS: Results are expected in 2024. CONCLUSION: TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.

The effect of a high-selenium lentil diet on cardiovascular risk markers in an arsenic-exposed population.

Chronic arsenic exposure is associated with a number of systemic diseases, including cardiovascular disease. Selenium has been shown to promote arsenic excretion from the body. We investigated if a high-selenium lentil diet has an effect on blood pressure and plasma lipid levels in an arsenic-exposed population by conducting a 6-month randomized controlled dietary intervention trial with 405 participants.

Toxicity of Refugio Beach Oil to Sand Crabs (Emerita analoga), Blue Mussels (Mytilus sp.), and Inland Silversides (Menidia beryllina).

Monterey formation crude oil spilled from an onshore pipeline and entered the surf zone near Refugio State Beach, Santa Barbara County, California (USA) on 19 May 2015. During this season, early life stages of many marine fish and invertebrates were present. Surf zone water and beach porewater samples were collected during the 4 mo after the spill and 2 yr later for chemical analyses. Elevated polycyclic aromatic hydrocarbon (PAH) and total petroleum hydrocarbon concentrations were observed in surf zone water and porewater near the release point, declining with distance and time. Early life stage toxicity was investigated by conducting 6- and 7-d static renewal bioassays with sand crab (Emerita analoga) post larvae (megalopae) and inland silverside larvae (Menidia beryllina), respectively, and a 48-h blue mussel (Mytilus sp.) embryo development bioassay. Dilutions of a high-energy water accommodated fraction of the Refugio Beach oil and a seawater control were prepared to simulate surf zone PAH concentrations (nominal PAH45 ; 0, 0.5, 1, 5, 10, 50, 100, and 500 µg/L). The PAH45 median lethal concentrations (LC50s), based on measured concentrations, were 381 µg/L for Mytilus sp., 75.6 µg/L for Menidia, and 40.9 µg/L for Emerita. Our results suggest that PAH concentrations in coastal waters of the spill-affected area were potentially lethal to early life stages of fish and invertebrates. Environ Toxicol Chem 2021;40:2578-2586. © 2021 SETAC.

Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy.

The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between- and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence. These findings provide key insights into the underlying molecular determinants of clinical CAR T-cell function. SIGNIFICANCE: To improve clinical outcomes for CAR T-cell therapy, there is a need to understand the molecular determinants of CAR T-cell persistence. These data represent the largest clinically annotated molecular atlas in CAR T-cell therapy to date, and significantly advance our understanding of the mechanisms underlying therapeutic efficacy.This article is highlighted in the In This Issue feature, p. 2113.

Opioid-Induced Constipation and Acupuncture: A Case Discussion.

BACKGROUND: Use of acupuncture for treatment of functional constipation is well studied; however, studies examining use of acupuncture for opioid-induced constipation are limited. CASE DESCRIPTION: A 70-year-old woman with newly diagnosed multiple myeloma discovered after presentation to the emergency room with severe back pain. Pain management required use of opioids, escalating to effect. Hospital course was complicated by opioid-induced constipation causing abdominal pain, nausea, and ileus despite aggressive titration of stimulant and osmotic laxatives as well as administration of suppositories and enemas on multiple occasions. Prior to nasogastric tube placement for the ileus, the patient requested acupuncture treatment in attempt to relieve constipation. Shortly after acupuncture session, patient passed multiple stools with improvement in abdominal pain and nausea and avoidance of nasogastric tube. CONCLUSION: Acupuncture for opioid-induced constipation may provide symptom relief through use of nonpharmacologic interventions; however, further studies are needed to determine the optimal therapeutic approach.

Clinical randomized trial study of hearing aids effectiveness in association with Ginkgo biloba extract (EGb 761) on tinnitus improvement / Estudo clínico randomizado da eficácia da prótese auditiva associada ao extrato de Ginkgo biloba (EGb 761) na melhoria do zumbido

Abstract Introduction: Tinnitus is defined as the perception of sound without its actual presence in the environment. It has been the subject of a great number of studies, especially considering its consequences on patient's quality of life. Objective: This study aimed to investigate the effect of hearing aids and/or Ginkgo biloba extract EGb 761 on tinnitus in patients with hearing loss. Methods: This is a trial randomized-controlled treatment, parallel, double-blind, with three-arm. Thirty-three adults subjects were divided into three groups: group 1 — subjects undergoing drug therapy with Ginkgo biloba extract EGb 761; group 2 — individuals fitted with digital hearing aids; group 3 — individuals submitted to drug therapy with Ginkgo biloba extract EGb 761 and using hearing aids. The tinnitus handicap inventory and visual analogue scale were used to evaluate self-perception of tinnitus loudness and severity before treatment and 90 days after treatment. Results: This study demonstrated a significant correlation between tinnitus handicap inventory and visual analogue scale, before and after treatment. We observed a significant improvement in self-perception of tinnitus loudness and severity after 90 days of treatment with Ginkgo biloba extract EGb 761 and/or hearing aids. No correlation was found between tinnitus onset time and self-perception of tinnitus loudness and severity. Hearing aids were more effective in patients with a shorter tinnitus onset time and Ginkgo biloba extract was effective regardless of tinnitus duration. Conclusions: It was possible to prove the effectiveness of the hearing aids and/or Ginkgo biloba extract EGb 761 treatment, which shows success in the control of tinnitus contributing to the improvement of this symptom.

Resumo Introdução: O zumbido é definido como a percepção de um som sem a sua presença real no ambiente e tem sido objeto de um grande número de estudos, especialmente devido às suas consequências na qualidade de vida do paciente. Objetivo: Investigar o efeito de próteses auditivas e/ou extrato de Ginkgo biloba EGb 761 sobre o zumbido em pacientes com perda auditiva. Método: Ensaio clínico randomizado controlado, paralelo, duplo-cego, com três braços. Trinta e três indivíduos adultos foram divididos em três grupos: Grupo 1 - indivíduos submetidos à terapia medicamentosa com extrato de Ginkgo biloba EGb 761; Grupo 2 - indivíduos equipados com próteses auditivas digitais; Grupo 3 - indivíduos submetidos à terapia medicamentosa com extrato de Ginkgo biloba EGb 761 e próteses auditivas. O Tinnitus handicap inventory e a escala visual analógica foram usados para avaliar a autopercepção de intensidade e da gravidade do zumbido antes do tratamento e 90 dias após o tratamento. Resultados: Este estudo demonstrou uma correlação significante entre o Tinnitus handicap inventory e a escala visual analógica, antes e após o tratamento. Observou-se melhoria significativa na autopercepção de loudness e da intensidade do zumbido após 90 dias de tratamento com extrato de Ginkgo biloba EGb 761 e/ou prótese auditiva. Não foi encontrada correlação entre o tempo de início do zumbido e a autopercepção da intensidade e gravidade do zumbido. As próteses auditivas foram mais eficazes em pacientes com menor tempo de início de zumbido e o extrato de Ginkgo biloba foi eficaz, independentemente da duração do zumbido. Conclusões: Foi possível comprovar a eficácia do tratamento com a prótese auditiva e/ou extrato de Ginkgo biloba EGb 761, o que demonstra sucesso no controle do zumbido e contribui para a melhoria desse sintoma.

Effects of Aerobic Training Versus Breathing Exercises on Asthma Control: A Randomized Trial.

BACKGROUND: Aerobic training and breathing exercises are interventions that improve asthma control. However, the outcomes of these 2 interventions have not been compared. OBJECTIVE: To compare the effects of aerobic training versus breathing exercises on clinical control (primary outcome), quality of life, exercise capacity, and airway inflammation in outpatients with moderate-to-severe asthma. METHODS: Fifty-four asthmatics were randomized into either the aerobic training group (AG, n = 29) or the breathing exercise group (BG, n = 25). Both interventions lasted for 24 sessions (2/week, 40 minutes/session). Asthma clinical control (Asthma Control Questionnaire [ACQ]), quality of life (Asthma Quality of Life Questionnaire), asthma symptom-free days (ASFD), airway inflammation, exercise capacity, psychological distress (Hospital Anxiety and Depression Scale), daily-life physical activity (DLPA), and pulmonary function were evaluated before, immediately after, and 3 months after the intervention. RESULTS: Both interventions presented similar results regarding the ACQ score, psychological distress, ASFD, DLPA, and airway inflammation (P > .05). However, participants in the AG were 2.6 times more likely to experience clinical improvement at the 3-month follow-up than participants in the BG (P = .02). A greater proportion of participants in the AG also presented a reduction in the number of days without rescue medication use compared with BG (34% vs 8%; P = .04). CONCLUSIONS: Outpatients with moderate-to-severe asthma who participated in aerobic training or breathing exercise programs presented similar results in asthma control, quality of life, asthma symptoms, psychological distress, physical activity, and airway inflammation. However, a greater proportion of participants in the AG presented improvement in asthma control and reduced use of rescue medication.

Deposition of Iron in the Bone Marrow of a Murine Model of Hematopoietic Acute Radiation Syndrome.

Exposure to high-dose total body irradiation (TBI) can result in hematopoietic acute radiation syndrome (H-ARS), characterized by leukopenia, anemia, and coagulopathy. Death from H-ARS occurs from hematopoietic insufficiency and opportunistic infections. Following radiation exposure, red blood cells (RBCs) undergo hemolysis from radiation-induced hemoglobin denaturation, causing the release of iron. Free iron can have multiple detrimental biological effects, including suppression of hematopoiesis. We investigated the impact of radiation-induced iron release on the bone marrow following TBI and the potential impact of the ACE inhibitor captopril, which improves survival from H-ARS. C57BL/6J mice were exposed to 7.9 Gy, 60Co irradiation, 0.6 Gy/min (LD70-90/30). RBCs and reticulocytes were significantly reduced within 7 days of TBI, with the RBC nadir at 14-21 days. Iron accumulation in the bone marrow correlated with the time course of RBC hemolysis, with an ∼10-fold increase in bone marrow iron at 14-21 days post-irradiation, primarily within the cytoplasm of macrophages. Iron accumulation in the bone marrow was associated with increased expression of genes for iron binding and transport proteins, including transferrin, transferrin receptor 1, ferroportin, and integrin αMß2. Expression of the gene encoding Nrf2, a transcription factor activated by oxidative stress, also increased at 21 days post-irradiation. Captopril did not alter iron accumulation in the bone marrow or expression of iron storage genes, but did suppress Nrf2 expression. Our study suggests that following TBI, iron is deposited in tissues not normally associated with iron storage, which may be a secondary mechanism of radiation-induced tissue injury.

Clinical randomized trial study of hearing aids effectiveness in association with Ginkgo biloba extract (EGb 761) on tinnitus improvement.

INTRODUCTION: Tinnitus is defined as the perception of sound without its actual presence in the environment. It has been the subject of a great number of studies, especially considering its consequences on patient's quality of life. OBJECTIVE: This study aimed to investigate the effect of hearing aids and/or Ginkgo biloba extract EGb 761 on tinnitus in patients with hearing loss. METHODS: This is a trial randomized-controlled treatment, parallel, double-blind, with three-arm. Thirty-three adults subjects were divided into three groups: group 1 - subjects undergoing drug therapy with Ginkgo biloba extract EGb 761; group 2 - individuals fitted with digital hearing aids; group 3 - individuals submitted to drug therapy with Ginkgo biloba extract EGb 761 and using hearing aids. The tinnitus handicap inventory and visual analogue scale were used to evaluate self-perception of tinnitus loudness and severity before treatment and 90 days after treatment. RESULTS: This study demonstrated a significant correlation between tinnitus handicap inventory and visual analogue scale, before and after treatment. We observed a significant improvement in self-perception of tinnitus loudness and severity after 90 days of treatment with Ginkgo biloba extract EGb 761 and/or hearing aids. No correlation was found between tinnitus onset time and self-perception of tinnitus loudness and severity. Hearing aids were more effective in patients with a shorter tinnitus onset time and Ginkgo biloba extract was effective regardless of tinnitus duration. CONCLUSIONS: It was possible to prove the effectiveness of the hearing aids and/or Ginkgo biloba extract EGb 761 treatment, which shows success in the control of tinnitus contributing to the improvement of this symptom.